Composition for the treatment of nasopharyngeal carcinoma and method of use thereof

ABSTRACT

Disclosed is a novel drug combination which is useful for the treatment of nasopharyngeal carcinoma, said novel drug combination comprising one or more of a farnesyl transferase inhibitor and one or more of an anthracyline.

BACKGROUND OF THE INVENTION

Nasopharyngeal carcinoma (NPC), a human squamous cell cancer, arises inthe surface epithelium of the posterior nasopharynx. (Liao, W. C., etal., Int. J. of Oncology 17: 323-328 (2000)). Undifferentiated NPC'shave several remarkable features which make them unique among humanepithelial malignancies. (Ablashi, D., et al., Epstein-Barr virus andKaposi's sarcoma Herpesvirus/Human Herpesvirus 8 IARC monographs on theevaluation of carcinogenic risks to humans. IARC, Lyon, France,n^(o)70:97.) They are rare in most countries but they occur with a highincidence in some selected areas, especially Southeast Asia and NorthAfrica.

NPC is consistently associated with the Epstein-Barr virus (EBV)regardless of patient geographic origin. On tissue sections, NPC appearsto be heavily infiltrated by non-malignant lymphocytes mostly of theT-lineage. The full length genome of EBV is contained in all malignantepithelial cells and consistently encodes several viral products whichare likely to contribute to the malignant phenotype. However, there isno production of viral particles in tumor cells; in other words, NPCcells are mainly in a state of “latent” EBV-infection. Some of thelatent viral products are the EBNA1 protein and two species of smalluntranslated RNA's, called EBER 1 and 2. Another EBV-protein calledLatent Membrane Protein 1 (LMP1) is produced in about 50% of NPC's.Other viral RNA messengers and their corresponding proteins are underinvestigation. (Fries, K. L., et al., Identification of a novel proteinencoded by the BamHI A region of the Epstein-Barr virus. J Virol, 71:2765-2771, 1997; Kienzle, N., et al., Epstein-Barr virus-encodedRK-BARF0 protein expression. J Virol, 73: 8902-8906, 1999; Decaussin,G., et al., Expression of BARF1 gene encoded by Epstein-Barr virus innasopharyngeal carcinoma biopsies. Cancer Res, 60: 5584-5588, 2000.) NPConcogenesis is also promoted by cellular gene alterations. Inactivationof the p16/INK4 gene by point mutations or hypermethylation is the mostconsistent of these alterations. (Lo, K. W., et al., Hypermethylation ofthe p16 gene in nasopharyngeal carcinoma. Cancer Res, 56: 2721-2725,1996.) Small homozygous deletions or losses of heterozygocity frequentlyoccur in chromosome 3p suggesting that this region contains atumor-suppressor gene which is critical for NPC-oncogenesis. (Lo, K. W.,et al., High resolution allelotype of microdissected primarynasopharyngeal carcinoma. Cancer Res, 60: 3348-3353, 2000.) In contrastwith data recorded in most other human epithelial malignancies, p53 israrely mutated in NPC. (Effert, P., et al., Alterations of the p53 genein nasopharyngeal carcinoma. J Virol, 66: 3768-3775, 1992.) A functionalinactivation of p53 has been suspected by some authors but the mechanismof this potential inactivation remains to be elucidated. (Fries, K. L.et al., Epstein-Barr virus latent membrane protein 1 blocks p53-mediatedapoptosis through the induction of the A20 gene. J Virol, 70: 8653-8659,1996.)

Malignant NPC cells have a short doubling time and a high metastaticpotential. Nevertheless, they are prone to enter apoptosis both in situand in vitro. In the majority of cases, the apoptotic index is high ontissue sections of NPC's. (Harn, H. J., et al., Apoptosis innasopharyngeal carcinoma as related to histopathological characteristicsand clinical stage. Histopathology, 33: 117-122, 1998.) In addition, ithas been shown that NPC cells strongly express CD95 and are highlysensitive to CD95-mediated apoptosis in vitro. (Sbih-Lammali, F., etal., Control of apoptosis in Epstein Barr virus-positive nasopharyngealcarcinoma cells: opposite effects of CD95 and CD40 stimulation. CancerRes, 59: 924-930, 1999.) Vulnerability to apoptosis may in part explainwhy NPC's have a higher sensitivity to radiotherapy and chemotherapythan most other head and neck carcinomas. Radiotherapy is the basictherapeutic arm for treatment of the primary tumors, but in a growingnumber of cases it is combined with induction, concomitant or adjuvantchemotherapy. (Ali, H. et al., Chemotherapy in advanced nasopharyngealcancer. Oncology (Huntingt), 14:1223-1230, 2000.) Short term results ofinduction chemotherapy are often remarkable. The rate of completeremissions is routinely of 10 to 25% following two to three courses ofinduction chemotherapy. (Benasso, M., et al., Induction chemotherapyfollowed by alternating chemo-radiotherapy in stage 1V undifferentiatednasopharyngeal carcinoma. Br J Cancer, 83: 1437-1442, 2000; Chua, D. T.,et al., Patterns of failure after induction chemotherapy andradiotherapy for locoregionally advanced nasopharyngeal carcinoma: theQueen Mary Hospital experience. Int J Radiat Oncol Biol Phys, 49:1219-1228, 2001.) In some studies, the rate of complete lymph noderegressions can reach 50%. (Frikha, M., et al., Evaluation of tumoraland lymph node response to neoadjuvant chemotherapy in undifferentiatednasopharyngeal carcinoma, Bull Cancer, 84: 273-276, 1997.) However,these good responses are unpredictable and often of short duration. Inaddition, in only a few studies were good short term responses toinduction chemotherapy associated with some improvement in long termsurvival. (Benasso, M., et al., Induction chemotherapy followed byalternating chemo-radiotherapy in stage IV undifferentiatednasopharyngeal carcinoma. Br J Cancer, 83: 1437-1442, 2000.)

So far, despite its major role in the treatment of NPC, the effects ofchemotherapy on EBV-positive NPC cells have been poorly investigated.One major reason is the extreme difficulty of growing NPC cells invitro. For several decades the only source of experimental NPC materialswere tumor lines propagated into nude mice as xenografts and only asmall fraction of clinical NPC specimens could be successfully grafted.(Busson, P., et al., Establishment and characterization of threetransplantable EBV-containing nasopharyngeal carcinomas. Int J Cancer,42:599-606, 88.) More recently, there were reports of NPC cell linespropagated in vitro but many of these lines do not contain EBV, thus maynot be truly representative of in vivo NPC cells. (Lin, C. T., et al.,Association of Epstein-Barr virus, human papilloma virus, andcytomegalovirus with nine nasopharyngeal carcinoma cell lines. LabInvest, 71:731-736., 1994.) Significant progress was made by derivationfrom a Chinese NPC xenograft called Xeno-666, of a subclone calledC666-1 which can be permanently grown in vitro and which retains the EBVgenome. (Cheung, S. T., et al., Nasopharyngeal carcinoma cell line(C666-1) consistently harbouring Epstein-Barr virus. Int J Cancer,83:121-126, 1999.) We have also made progress in improving short term invitro cultures of cells derived from other NPC xenografts, especiallythe C15 North African NPC xenograft.

The biological mechanisms which underlie the cytotoxic effects ofanti-neoplastic drugs in NPC cells has yet to be fully elucidated. Thereare few reports in the literature on this topic and these have beenfocused mainly on the effects of cisplatin and taxol. Cisplatin wasshown to induce growth arrest in the CNE1 NPC cell line atconcentrations of about 1 μM. This growth arrest was accompanied byincreased expression of senescence-associated β-galactosidase. (Wang,X., et al., Evidence of cisplatin-induced senescent-like growth arrestin nasopharyngeal carcinoma cells. Cancer Res, 58: 5019-5022, 1998;Wang, X., et al., Mechanism of differential sensitivity to cisplatin innasopharyngeal carcinoma cells. Anticancer Res, 21: 403-408, 2001.)Taxol was shown to induce growth arrest and/or apoptosis in TWO1 andTWO39 NPC cell lines. (Lou, P. J. et al., Taxol reduces cytosolicE-cadherin and beta-catenin levels in nasopharyngeal carcinoma cell lineTW-039: cross-talk between the microtubule- and actin-basedcytoskeletons. J Cell Biochem, 79: 542-556, 2000; Huang, T. S., et al.,Activation of MAD 2 checkprotein and persistence of cyclin B1/CDC 2activity associate with paclitaxel-induced apoptosis in humannasopharyngeal carcinoma cells. Apoptosis, 5:235-241, 2000.)Significantly, however, the foregoing studies were performed onEBV-negative cell lines which either had been derived from rare forms ofEBV-negative differentiated NPC's (CNE1, TW039), or had lost theEBV-genome after a few passages in vitro (TWO1). (Lin, C. T., et al.,Association of Epstein-Barr virus, human papilloma virus, andcytomegalovirus with nine nasopharyngeal carcinoma cell lines. LabInvest, 71:731-736., 1994.) Thus the target cell lines of the foregoingstudies cannot be regarded as truly representative of undifferentiatedEBV-positive NPC's.

Testing anti-neoplastic drugs on genuine EBV-positive NPC cells in vitrorecently was made possible by technical developments in the handling ofthe C666-1 and C15 NPC tumor lines. As noted above, C666 was derivedfrom the xeno 666 transplanted NPC. C666 was subsequently subcloned inorder to stabilize its association with the EBV-genome, C666-1 being oneof the resulting clones. In contrast, a permanent in vitro cell line hasyet to be derived from the C15 transplanted NPC. However the selectivein vitro growth of malignant C15 cells can be and was obtained throughthe use of a PolyHema matrix. The PolyHema matrix prevented theproliferation of murine fibroblasts and allowed for the proliferation ofC15 cells in the form of small floating aggregates.

Farnesyl Tranferase Inhibitors (FTI's)

Farnesyl tranferase inhibitors (FTI's) are molecularly targeted drugswhich have been observed to induce malignant cell apoptosis in someexperimental systems. There are some indications that FTI's can increasethe benefit of chemotherapy or radiotherapy without a parallel increasein undesirable side-effects. (Moasser, M. M. et al., Farnesyltransferase inhibitors cause enhanced mitotic sensitivity to taxol andepothilones. Proc Natl Acad Sci USA, 95:1369-1374, 1998; Sebti, S. M. etal., Farnesyltransferase and geranylgeranyltransferase I inhibitors andcancer therapy: lessons from mechanism and bench-to-bedsidetranslational studies. Oncogene, 19: 6584-6593, 2000.) Although FTI'swere initially designed to inhibit the farnesylation and membraneanchoring of ras proteins, it is now clear that they interfere withfarnesylation of other proteins, as well, especially Rho B, rap 2, andlamin A and B. Cell treatment with FTI's has been observed to result inthe accumulation of geranylated Rho B which induces apoptosis oftransformed cells. (Prendergast, G. C. et al., Farnesyltransferaseinhibitors: antineoplastic properties, mechanisms of action, andclinical prospects. Semin Cancer Biol, 10: 443-452., 2000.) In othercellular models FTI's have been shown to inhibit the PI-3 kinasepathway. (Plo, I., et al., The phosphoinositide 3-kinase/Akt pathway isactivated by daunorubicin in human acute myeloid leukemia cell lines.FEBS Lett, 452: 150-154., 1999.)

Anthracyclins

Anthracyclins such as doxorubicin classically exert their cytotoxiceffect by inducing production of reactive oxygen species (ROS). ROS caninduce DNA lesions, p53 activation resulting in up-regulation ofp21/wafl, GADD 45, CD95 and Bax. (Kostic, C. et al., Isolation andcharacterization of sixteen novel p53 response genes. Oncogene, 19:3978-3987., 2000.) ROS also have some impact on membrane lipids and caninduce production of lipid second messengers. (Bettaieb, A., et al.,Daunorubicin- and mitoxantrone-triggered phosphatidylcholine hydrolysis:implication in drug-induced ceramide generation and apoptosis. MolPharmacol, 55: 118-125., 1999.)

Presently it is difficult to know where and how the FTI- anddoxorubicin-modified pathways intersect in such a way that they induceapoptosis. It has been postulated that caspase 8 is a key-effector ofTRAF1-cleavage during CD-95-mediated apoptosis. (Leo, E., et al., TRAF1is a substrate of caspases activated during tumor necrosis factorreceptor-α induced apoptosis. J Biol Chem, 55:8087-8093, 2000.) However,the cleavage of TRAF1 induced by drugs has some distinct features whencompared to the cleavage induced by CD95-agonists. Among these featuresis a sustained high ratio of uncleaved to cleaved forms of TRAF-1 indrug-treated samples, suggesting that an increase in TRAF1 productionoccurs in drug-treated NPC cells in parallel with the cleavage process.Interestingly, the same high ratio of cleaved to uncleaved molecules wasreported by Leo et al. for the HT1080 cell line expressing exogenousTRAF1 and treated by doxorubicin. (Id.) TRAF1 has a very restrictedtissue distribution. As in the case of EBV-transformed B-lymphocytes thestrong expression of TRAF1 in NPC is likely to be related to thepresence of EBV. (Mosialos, G., et al., The Epstein-Barr virustransforming protein LMP1 engages signaling proteins for the tumornecrosis factor receptor family. Cell, 80: 389-399, 1995.) Thus cleavageof TRAF1 would be a useful marker for specifically monitoringchemo-induced apoptosis in NPC cells, for example in biopsy material.

In the cell viability assay, below, both C15 and C666-1 were observed tobe remarkably sensitive to the cytotoxic effects of doxorubicin atconcentrations below 1 μM. However, neither doxorubicin nor taxolinduced apoptosis on its own. Interestingly, doxombicin was included inthe combination of drugs that had achieved a marked—althoughtransient—tumor regression in the patient who was the donor of the C15tumor line.

Doxorubicin was combined with FTI's in order to achieve chemo-inducedapoptosis of NPC cells and to increase cytotoxicity. Compound A is aselective inhibitor of the farnesyl-transferase enzyme having thefollowing structure:

The cytotoxic effect of doxorubicin against both C15 and C666-1 cellswas dramatically enhanced when it was used in combination with CompoundA. The cytotoxic effect of against C15 cells was associated with massiveapoptosis, associated with early cleavage of TRAF1, 48 h after startingcell exposure to the combination. The cytotoxic effect against C666-1cells was associated with growth arrest and non-characterized celldeath, apoptotic events not being observed at the tested concentrations.

It is noteworthy that in the same assay, below, both C15 cells and evenmore noticeably C666-1 cells were less sensitive to cis-platin than todoxorubicin. This result is consistent with a previous report of poorsensitivity of C666-1 cells to cis-platinum in a short term cytotoxicityassay. (Weinrib, L., et al., Cisplatin chemotherapy plus adenoviral p53gene therapy in EBV-positive and -negative nasopharyngeal carcinoma.Cancer Gene Ther, 8: 352-360., 2001.) These results are surprising sincecis-platinum is currently regarded as the most effective agent in thechemotherapy of NPC's. (Ali, H. et al., Chemotherapy in advancednasopharyngeal cancer. Oncology (Huntingt), 14: 1223-1230, 2000.)

SUMMARY OF THE INVENTION

In a first aspect the present invention features a pharmaceuticalcomposition comprising a farnesyl transferase inhibitor, a prodrugthereof or a pharmaceutically acceptable salt of said farnesyltransferase inhibitor or of said farnesyl transferase inhibitor prodrug,and an anthracycline, a prodrug thereof or a pharmaceutically acceptablesalt of said anthracycline or of said anthracycline prodrug.

According to a first preferred embodiment of the first aspect of theinvention said farnesyl transferase inhibitor is a compound which isdisclosed in International Patent Application Publication No. WO00/39130; i.e., a compounds according to formula I:

wherein

n1 is 0 or 1;

X is, independently for each occurrence,(CHR¹¹)_(n3)(CH₂)_(n4)Z(CH₂)_(n5); Z is O, N(R¹²), S, or a bond;

n3 is, independently for each occurrence, 0 or 1;

n4 and n5 each is, independently for each occurrence, 0, 1, 2, or 3;

Y is, independently for each occurrence, CO, CH₂, CS, or a bond;

R¹ is

or N²⁴R²⁵);

R², R¹¹, and R¹² each is, independently for each occurrence, H or anoptionally substituted moiety selected from the group consisting of(C₁₋₆)alkyl and aryl, wherein said optionally substituted moiety isoptionally substituted with one or more of R⁸ or R³⁰;

R³ is, independently for each occurrence, H or an optionally substitutedmoiety selected from the group consisting of (C₁₋₆)alkyl, (C₂₋₆)alkenyl,(C₂₋₆)alynyl, (C₃₋₆)cycloalkyl, (C₃₋₆)cycloalkyl(C₁₋₆)alkyl,(C₅₋₇)cycloalkenyl, (C₅₋₇)cycloalkenyl(C₁₋₆)alkyl, aryl,aryl(C₁₋₆)alkyl, heterocyclyl, and heterocyclyl(C₁₋₆)alkyl, wherein saidoptionally substituted moiety is optionally substituted with one or moreR³⁰;

R⁴ and R⁵ each is, independently for each occurrence, H or an optionallysubstituted moiety selected from the group consisting of (C₁₋₆)alkyl,(C₃₋₆)cycloalkyl, aryl, and heterocyclyl, wherein said optionallysubstituted moiety is optionally substituted with one or more R³⁰,wherein each said substituent is independently selected, or R⁴ and R⁵can be taken together with the carbons to which they are attached toform aryl;

R⁶ is, independently for each occurrence, H or an optionally substitutedmoiety selected from the group consisting of (C1-6)alkyl, (C₂₋₆)alkenyl,(C₃₋₆)cycloalkyl, (C₃₋₆)cycloalkyl(C₁₋₆)alkyl, (C₅₋₇)cycloalkenyl,(C₅₋₇)cycloalkenyl(C₁₋₆)alkyl, aryl, aryl(C₁₋₆)alkyl, heterocyclyl, andheterocyclyl(C₁₋₆)alkyl, wherein said optionally substituted moiety isoptionally substituted with one or more substituents each independentlyselected from the group consisting of OH, (C₁₋₆)alkyl, (C₁₋₆)alkoxy,—N(R⁸R⁹), —COOH, —CON(R⁸R⁹), and halo,

where R⁸ and R⁹ each is, independently for each occurrence, H,(C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₂₋₆)alkynyl, aryl, or aryl(C₁₋₆)alkyl;

R⁷ is, independently for each occurrence, H, ═O, ═S, or an optionallysubstituted moiety selected from the group consisting of (C₁₋₆)alkyl,(C₂₋₆)alkenyl, (C₃₋₆)cycloalkyl, (C₃₋₆)cycloalkyl(C₁₋₆)alkyl,(C₅₋₇)cycloalkenyl, (C₅₋₇)cycloalkenyl(C₁₋₆)alkyl, aryl,aryl(C₁₋₆)alkyl, heterocyclyl, and heterocyclyl(C₁₋₆)alkyl, wherein saidoptionally substituted moiety is optionally substituted with one or moresubstituents each independently selected from the group consisting ofOH, (C₁₋₆)alkyl, (C₁₋₆)alkoxy, —N(R⁸R⁹), —COOH, —CON(R⁸R⁹), and halo;

R¹⁰ is C; or when n1=0, R⁶ and R⁷ can be taken together with the carbonatoms to which they are attached to form aryl or cyclohexyl;

R²¹ is, independently for each occurrence, H or an optionallysubstituted moiety selected from the group consisting of (C₁₋₆)alkyl andaryl(C₁₋₆)alkyl, wherein said optionally substituted moiety isoptionally substituted with one or more substituents each independentlyselected from the group consisting of R⁸ and R³⁰;R²² is H, (C₁₋₆)alkylthio, (C₃₋₆)cycloalkylthio, R⁸—CO—, or asubstituent according to the formula

R²⁴ and R²⁵ each is, independently for each occurrence, H, (C₁₋₆)alkyl,or aryl(C₁₋₆)alkyl;

R³⁰ is, independently for each occurrence, (C₁₋₆)alkyl, —O—R⁸,—S(O)_(n6)R⁸, —S(O)_(n7)N(R⁸R⁹), —N(R⁸R⁹), —CN, —NO₂, —CO₂R⁸,—CON(R⁸R⁹), —NCO—R⁸, or halogen; n6 and n7 each is, independently foreach occurrence, 0, 1, or 2;

wherein said heterocyclyl is azepinyl, benzimidazolyl, benzisoxazolyl,benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl,benzothiazolyl, benzothienyl, benzoxazolyl, chromanyl, cinnolinyl,dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl,dihydrobenzothio-pyranyl sulfone, furyl, imidazolidinyl, imidazolinyl,imidazolyl, indolinyl, indolyl, isochromanyl, isoindolinyl,isoquinolinyl, isothiazolidinyl, isothiazolyl, isothiazolidinyl,morpholinyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, piperidyl,piperazinyl, pyridyl, pyridyl N-oxide, quinoxalinyl, tetrahydrofuryl,tetrahydroisoquinolinyl, tetrahydro-quinolinyl, thiamorpholinyl,thiamorpholinyl sulfoxide, thiazolyl, thiazolinyl, thienofuryl,thienothienyl, or thienyl; and

wherein said aryl is phenyl or naphthyl;

provided that:

when n1=1, R¹⁰ is C and R⁶ is H, then R¹⁰ and R⁷ can be taken togetherto form

when n1=1, R¹⁰ is C, and R⁷ is ═O, —H, or ═S, then R¹⁰ and R⁶ can betaken together to form

wherein X¹, X², and X³ each is, independently, H, halogen, —NO₂,—NCO—R⁸, —CO₂R⁸, —CN, or —CON(R⁸R⁹); andwhen R¹ is N(24R²⁵), then n3 is 1, n4 and n5 each is 0, Z is a bond, andR³ and R¹¹ can be taken together to form

wherein n2 is 1-6, and X⁴ and X⁵ each is, independently, H, (C₁₋₆)alkyl,or aryl,

or X⁴ and X⁵ can be taken together to form (C₃₋₆)cycloalkyl;

or a pharmaceutically acceptable salt thereof.

According to a second preferred embodiment of the first aspect of theinvention said farnesyl transferase inhibitor is a compound according toformula I, wherein:

N(R²⁴R²⁵); andX is CH(R¹¹)_(n3)(CH₂)_(n4) or Z, wherein when X is Z, Z is O, S, orN(R¹²);or a pharmaceutically acceptable salt thereof.

According to a first more preferred embodiment of said second preferredembodiment of the first aspect of the invention said farnesyltransferase inhibitor is a compound according to formula I, wherein:R¹ is

X is CH(R¹¹)_(n3)(CH₂)_(n4); andn1 is 0;or a pharmaceutically acceptable salt thereof.

According to a second more preferred embodiment of said second preferredembodiment of the first aspect of the invention said farnesyltransferase inhibitor is a compound according to formula I, wherein:

R¹ is

n3, n4, and n5 each is 0;Z is a bond;Y is, independently for each occurrence, CO or CS; andn1 is 0;or a pharmaceutically acceptable salt thereof.

According to a third more preferred embodiment of said second preferredembodiment of the first aspect of the invention said farnesyltransferase inhibitor is a compound according to formula I, wherein:R¹ is

R⁶ is H;n1 is 1;R⁷ and R¹⁰ are taken together to form

n3 is 1 and R¹¹ is H;Z is O or a bond;

-   n5 is 0; and-   Y is CO, CH₂, or a bond;    or a pharmaceutically acceptable salt thereof.

According to a fourth more preferred embodiment of said second preferredembodiment of the first aspect of the invention said farnesyltransferase inhibitor is a compound according to formula I, wherein:

R¹ is N(R²⁴R²⁵);

n1 is 0;

n3 is 1;

n4 is 0;

n5 is 0;

Y is CO or CS;

Z is a bond; and

R³ and R¹¹ are taken together to form

or a pharmaceutically acceptable salt thereof.

According to a fifth more preferred embodiment of said second preferredembodiment of the first aspect of the invention said farnesyltransferase inhibitor is a compound according to formula L wherein:R¹ is

R⁷ is H or ═O;n1 is 1;R⁶ and R¹⁰ are taken together to form

n3 is 1 and R¹¹ is H;n5 is 0;Y is CO or CH₂; andZ is O or a bond;or a pharmaceutically acceptable salt thereof.

According to a third preferred embodiment of the first aspect of theinvention said farnesyl transferase inhibitor is a compound according toformula I, wherein said compound is:

-   8-butyl-7-(3-(imidazol-5-yl)-1-oxopropyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;-   8-butyl-2-(2-hydroxyphenyl)-7-(imidazol-4-yl-propyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;-   8-butyl-7-(4-imidazolylpropyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;-   7-(2-(imidazol-4-yl)-1-oxo-ethyl)-2-(2-methoxyphenyl)-8-(1-methylpropyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;-   2-(2-methoxyphenyl)-8-(1-methylpropyl)-7-(1-oxo-2-(1-(phenylmethyl)-imidazol-S-yl)ethyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;-   2-(2-methoxyphenyl)-8-(1-methylpropyl)-7-(2-(1-phenylmethyl)-imidazol-5-yl)ethyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;-   7-(2-(1-(4-cyanophenylmethyl)-imidazol-5-yl)-1-oxo-ethyl)-2-(2-methoxyphenyl)-8-(1-methylpropyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;-   7-((1H-imidazol-4-yl)methyl)-2-(2-methoxyphenyl)-8-(1-methylpropyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;-   7-((4-imidazolyl)carbonyl)-2-(2-methoxyphenyl)-8-(1-methylpropyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;-   7-(1-(4-cyanophenylmethyl)-imidazol-5-yl)methyl-2-(2-methoxyphenyl)-8-(1-methylpropyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;-   7-(2-(4-cyanophenyhnethyl)-imidazol-5-yl)-1-oxo-ethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine;-   5-butyl-7-(2-(4-cyanophenyhnethylimidazol-5-yl)-1-oxo-ethyl)-2-phenyl-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;-   6-butyl-7-(2-(4-cyanophenylmethylimidazol-5-yl)-1-oxo-ethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine;-   6-butyl-7-(2-(4-cyanophenylmethylimidazol-5-yl)-1-oxo-ethyl)-2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine;-   5-butyl-7-(2-(1-(4-cyanophenylmethyl)-imidazole-5-yl)-1-oxo-ethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;-   7-(2-(1-(4-cyanophenylmethyl)-imidazole-5-yl)-1-oxo-ethyl)-8-(cyclohexylmethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;-   5-butyl-7-(2-(1H-imidazole-5-yl)-1-oxo-ethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;-   7-(2-(4-cyanophenylmethyl)-imidazol-5-yl)-1-oxo-ethyl)-2-(2-(phenylmethoxy)-phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine;    or-   2-(2-butoxyphenyl)-7-(2-(4-cyanophenylmethyl)-imidazol-5-yl)-1-oxo-ethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine;    or a pharmaceutically acceptable salt thereof.

According to a fourth preferred embodiment of the first aspect of theinvention said farnesyl transferase inhibitor is a compound according toformula I, wherein said compound is:

-   1,2-dihydro-1-((1H-imidazol-4-yl)methyl)-4-(2-methoxyphenyl)-imidazo[1,2-c][1,4]benzodiazepine;-   1-(2-(1-(4-cyanophenylmethyl)imidazol-4-yl)-1-oxoethyl)-1,2-dihydro-4-(2-methoxyphenyl)-imidazo[1,2-c][1,4]benzodiazepine;-   9-bromo-1-(2-(1-(4-cyanophenylmethyl)imidazol-4-yl)-1-oxoethyl)-1,2-dihydro-4-(2-methoxyphenyl)-imidazo[1,2-c][1,4]benzodiazepine;-   9-Chloro-1-(2-(1-(4-cyanophenylmethyl)imidazol-4-yl)-1-oxoethyl)-1,2-dihydro-4-(2-methoxyphenyl)-imidazo[1,2-c][1,4]benzodiazepine;-   10-Bromo-1-(2-(1-(4-cyanophenylmethyl)imidazol-4-yl)-1-oxoethyl)-1,2-dihydro-4-(2-methoxyphenyl)-imidazo[1,2-c][1,4]benzodiazepine;-   1-(2-(1-(4-cyanophenylmethyl)imidazol-4-yl)-1-oxoethyl)-1,2-dihydro-8-fluoro-4-(2-methoxyphenyl)-imidazo[1,2-c][1,4]benzodiazepine;    or    or a pharmaceutically acceptable salt thereof.

According to a more preferred embodiment of said fourth preferredembodiment of the first aspect of the invention said farnesyltransferase inhibitor is a compound according to formula I, wherein saidcompound is:

-   1-(2-(1-(4-cyanophenylmethyl)imidazol-4-yl)-1-oxoethyl)-1,2-dihydro-4-(2-methoxyphenyl)-imidazo[1,2-c][1,4]benzodiazepine;-   9-bromo-1-(2-(1-(4-cyanophenylmethyl)imidazol-4-yl)-1-oxoethyl)-1,2-dihydro-4-(2-methoxyphenyl)-imidazo[1,2-c][1,4]benzodiazepine;-   9-Chloro-1-(2-(1-(4-cyanophenylmethyl)imidazol-4-yl)-1-oxoethyl)-1,2-dihydro-4-(2-methoxyphenyl)-imidazo[1,2-c][1,4]benzodiazepine;-   10-Bromo-1-(2-(1-(4-cyanophenylmethyl)imidazol-4-yl)-1-oxoethyl)-1,2-dihydro-4-(2-methoxyphenyl)-imidazo[1,2-c][1,4]benzodiazepine;-   1-(2-(1-(4-cyanophenylmethyl)imidazol-4-yl)-1-oxoethyl)-1,2-dihydro-8-fluoro-4-(2-methoxyphenyl)-imidazo[1,2-c][1,4]benzodiazepine;

According to a fifth preferred embodiment of the first aspect of theinvention said farnesyl transferase inhibitor is a compound according toformula I, wherein said compound is:

-   7-(2-amino-1-oxo-3-thiopropyl)-8-(mercaptoethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine    disulfide;    or a pharmaceutically acceptable salt thereof.

According to a sixth preferred embodiment of the first aspect of theinvention said farnesyl transferase inhibitor is a compound according toformula I, wherein said compound is:

-   5-(2-(1-(4-cyanophenylmethyl)-imidazol-5-yl)-1-oxo-ethyl)-5,6-dihydro-2-phenyl-1H-imidazo[1,2-a][1,4]benzodiazepine;    or a pharmaceutically acceptable salt thereof.

According to a seventh preferred embodiment of the first aspect of theinvention said farnesyl transferase inhibitor is a compound according toformula I, wherein said compound is:

-   1,2-dihydro-1-(2-(imidazol-1-yl)-1-oxoethyl)-4-(2-methoxyphenyl)    imidazo[1,2a] [1,4]benzodiazepine;-   1,2-dihydro-4-(2-methoxyphenyl)-1-(2-(pyridin-3-yl)-1-oxoethyl)    imidazo[1,2a][1,4]benzodiazepine; or-   1,2-dihydro-4-(2-methoxyphenyl)-1-(2-(pyridin-4-yl)-1-oxoethyl)    imidazo[1,2a] [1,4]benzodiazepine;    or a pharmaceutically acceptable salt thereof.

According to an eighth preferred embodiment of the first aspect of theinvention said farnesyl transferase inhibitor is a compound according toformula I, wherein said compound is:

or a pharmaceutically acceptable salt thereof.

According to a ninth preferred embodiment of the first aspect of theinvention said farnesyl transferase inhibitor is a compound according toformula I, wherein said compound is:

or a pharmaceutically acceptable salt thereof.

According to a first more preferred embodiment of said ninth preferredembodiment of the first aspect of the invention said farnesyltransferase inhibitor is a compound according to formula L wherein saidcompound is:

or a pharmaceutically acceptable salt thereof.

A second more preferred embodiment of said ninth preferred embodimentcomprises said first more preferred embodiment of said eighth preferredembodiment wherein said anthracyclin is doxorubicin, daunorubicin,epirubicin, idarubicin, or amrubicin, or a pharmaceutically acceptablesalt thereof.

A third more preferred embodiment of said ninth preferred embodimentcomprises said second more preferred embodiment of said eighth preferredembodiment wherein said anthracyclin is doxorubicin, or apharmaceutically acceptable salt thereof.

In a preferred embodiment of the first aspect of the invention, and ofeach of said first through ninth preferred embodiments of said firstaspect of the invention, and of each of said more preferred embodimentsthereof, termed the tenth preferred embodiment of said first aspect ofthe invention, said anthracycline is doxorubicin, daunorubicin,epirubicin, idarubicin, or amrubicin, or a prodrug thereof, or apharmaceutically acceptable salt of said anthracyclin or of saidanthracyclin prodrug.

In a more preferred embodiment of said tenth preferred embodiment, saidanthracyclin is doxorubicin, or a pharmaceutically acceptable saltthereof.

In a second aspect the present invention features a pharmaceuticalcomposition according to said first aspect of the invention, oraccording to any one of said preferred embodiments of said first aspect,or according to any one of said more preferred embodiments of said firstaspect, and a pharmaceutically acceptable carrier, vehicle or diluent.

In a third aspect the present invention features a method of decreasingthe rate of proliferation of nasopharyngeal carcinoma cells, said methodcomprising contacting said nasopharyngeal cells with a farnesyltransferase inhibiting compound in combination with an anthracyclinecompound, separately or simultaneously, wherein each of said farnesyltransferase inhibiting compound and said anthracycline compound isselected from the farnesyl transferase inhibiting compounds theanthracycline compounds disclosed in the pharmaceutical compositionsaccording to said first aspect of the invention, or according to any oneof said preferred embodiments of said first aspect, or according to anyone of said more preferred embodiments of said first aspect.

In a first preferred embodiment of said third aspect the presentinvention features a method of decreasing the rate of proliferation ofnasopharyngeal carcinoma cells, said method comprising contacting saidnasopharyngeal cells with a pharmaceutical composition according to saidfirst aspect of the invention, or according to any one of said preferredembodiments of said first aspect, or according to any one of said morepreferred embodiments of said first aspect

In a second preferred embodiment of said third aspect the presentinvention features a method of treating nasopharyngeal carcinoma in apatient, said method comprising administering to said patient apharmaceutical composition according to said first aspect of theinvention, or according to any one of said preferred embodiments of saidfirst aspect, or according to any one of said more preferred embodimentsof said first aspect.

In a third preferred embodiment of said third aspect the presentinvention features a method of treating nasopharyngeal carcinoma in apatient, said method comprising administering to said patient effectiveamounts of one or more farnesyl transferase inhibitor in combinationwith one or more anthracycline, wherein said effective amounts of saidfarnesyl transferase inhibitor or inhibitors and of said anthracyclin oranthracyclines are effective in combination to treat said nasopharyngealcarcinoma.

In a fourth preferred embodiment of said third aspect, the inventionfeatures a method according to any one of said first, second or thirdpreferred embodiments of said fourth preferred embodiments wherein saidpatient is a mammal.

In a fifth preferred embodiment of said third aspect, the inventionfeatures a method according to any one of said first, second, third orfourth preferred embodiments of said third aspect wherein said patientis a human being.

In a sixth preferred embodiment of said third aspect, the inventionfeatures a method according to any one of said first, second, third,fourth or fifth preferred embodiments of said third aspect wherein afarnesyl transferase inhibitor and an anthracycline are administeredsubstantially simultaneously.

In a fourth aspect the invention features a pharmaceutical kitcomprising one or more of a farnesyl transferase inhibitor orpharmaceutically acceptable salt thereof and one or more of ananthracycline or pharmaceutically acceptable salt thereof andinstructions for use for the treatment of nasopharyngeal carcinoma.

In a first preferred embodiment of said fourth aspect of the inventionfeatures a kit comprising: a) a first unit dosage form comprising afarnesyl transferase inhibitor, a prodrug thereof or a pharmaceuticallyacceptable salt of said farnesyl transferase inhibitor or of saidfarnesyl transferase inhibitor prodrug and a pharmaceutically acceptablecarrier, vehicle or diluent; b) a second unit dosage form comprising ananthracycline, a prodrug thereof or a pharmaceutically acceptable saltof said anthracycline or of said anthracycline prodrug and apharmaceutically acceptable carrier, vehicle or diluent; and c) acontainer.

In a more preferred embodiment of said first preferred embodiment ofsaid fourth aspect of the invention is featured a kit wherein saidfarnesyl transferase inhibitor comprises a compound according to formulaI or a pharmaceutically acceptable salt thereof, and said anthracyclinecomprises doxorubicin, daunorubicin, epirubicin, idarubicin, oramrubicin or a pharmaceutically acceptable salt thereof.

In a still more preferred embodiment of said first preferred embodimentof said fourth aspect of the invention is featured a kit wherein saidfarnesyl transferase inhibitor comprises a compound according to theformula:

or a pharmaceutically acceptable salt thereof, and said anthracyclinecomprises doxorubicin or a pharmaceutically acceptable salt thereof.

The disclosure of International Patent Application Publication No. WO00/39130 teaches one or more methods of synthesizing compounds accordingto formula I.

According to another preferred aspect, the present invention relates toa drug combination comprising at least one anthracycline compound and atleast one farnesyl transferase inhibitor compound, wherein said farnesyltransferase inhibitor compound is described in one or more of thefollowing United States patents, the disclosure of each of which ishereby incorporated by reference in its entirety: U.S. Pat. Nos.6,455,523, 6,451,812, 6,441,017, 6,440,989, 6,440,974, 6,436,960,6,432,959, 6,426,352, 6,410,541, 6,403,581, 6,399,615, 6,387,948,6,387,905, 6,387,903, 6,384,061, 6,376,496, 6,372,747, 6,362,188,6,358,970, 6,358,968, 6,342,487, 6,329,376, 6,316,462, 6,300,501,6,297,249, 6,294,552, 6,277,854, 6,268,394, 6,268,378, 6,265,382,6,262,110, 6,258,824, 6,248,756, 6,242,458, 6,239,140, 6,228,865,6,228,856, 6,225,322, 6,218,406, 6,218,401, 6,214,828, 6,214,827,6,211,193, 6,194,438, 6,187,786, 6,174,903, 6,172,076, 6,160,015,6,159,984, 6,156,746, 6,150,377, 6,146,842, 6,143,758, 6,127,390,6,127,366, 6,124,295, 6,103,723, 6,103,487, 6,093,737, 6,090,948,6,090,944, 6,080,870, 6,080,769, 6,077,853, 6,075,025, 6,071,935,6,071,907, 6,066,738, 6,066,648, 6,063,930, 6,060,038, 6,054,466,6,051,582, 6,051,574, 6,048,861, 6,040,311, 6,040,305, 6,039,683,6,030,982, 6,028,201, 6,017,926, 6,015,817, 6,013,662, 6,001,835,5,998,407, 5,994,364, 5,990,277, 5,985,879, 5,981,562, 5,977,134,5,977,128, 5,972,984, 5,972,966, 5,972,942, 5,968,965, 5,965,609,5,965,578, 5,965,570, 5,962,243, 5,958,940, 5,958,939, 5,958,890,5,952,473, 5,948,781, 5,945,430, 5,945,429, 5,939,557, 5,939,439,5,939,416, 5,932,590, 5,929,077, 5,925,651, 5,925,648, 5,925,639,5,922,883, 5,919,785, 5,914,341, 5,891,872, 5,885,995, 5,883,105,5,880,140, 5,880,128, 5,877,177, 5,876,951, 5,874,452, 5,874,442,5,872,136, 5,872,135, 5,869,682, 5,869,275, 5,861,395, 5,859,035,5,859,015, 5,859,012, 5,856,439, 5,856,326, 5,854,265, 5,854,264,5,852,034, 5,852,010, 5,849,724, 5,837,224, 5,821,118, 5,817,678,5,807,853, 5,807,852, 5,801,175, 5,789,438, 5,780,492, 5,780,488,5,773,273, 5,756,528, 5,753,650, 5,736,539, 5,734,013, 5,728,703,5,721,236, 5,712,280, 5,710,171, 5,703,241, 5,703,090, 5,703,067,5,686,472, 5,684,013, 5,672,611, 5,663,193, 5,661,161, 5,661,152,5,661,128, 5,652,257, 5,635,363, 5,631,280, 5,627,202, 5,624,936,5,585,359, 5,578,629, 5,576,313, 5,576,293, 5,571,835, 5,567,729,5,536,750, 5,534,537, 5,525,479, 5,523,456, 5,510,371, 5,504,212,5,504,115, 5,491,164, and 5,480,893.

According to another preferred aspect, the present invention relates toa drug combination comprising at least one anthracycline compound and atleast one farnesyl transferase inhibitor compound, wherein said farnesyltransferase inhibitor compound is described in one or more of thefollowing United States patent publications, the disclosure of each ofwhich is hereby incorporated by reference in its entirety: 20020136744,20020128287, 20020120145, 20020119981, 20020107226, 20020103207,20020086884, 20020077301, 20020068742, 20020052380, 20020037889,20020037888, 20020022633, 20020019530, 20020019400, 20020010184,20020010176, 20020006967, 20010053853, 20010049113, 20010044938,20010039283, 20010039273, 20010016585, 20010014681, and 20010007870.

According to yet another preferred aspect, the present invention relatesto a drug combination comprising at least one anthracycline compound andat least one farnesyl transferase inhibitor compound, wherein saidfarnesyl transferase inhibitor compound is described in one or more ofthe following international patent applications and publications, thedisclosure of each of which is hereby incorporated by reference in itsentirety: WO02064142, WO02056884, WO02051835, WO02051834, WO0244164,WO0243733, WO0242296, WO0240015, WO0234247, WO0228409, WO0228381,WO0224687, WO0224686, WO0224683, WO0224682, WO0218368, WO0198302,WO0181322, WO0179180, WO0179179, WO0164252, WO0164246, WO0164226,WO0164218, WO0164217, WO0164199, WO0164198, WO0164197, WO0164196,WO0164195, WO0164194, WO0162727, WO0162234, WO0160815, WO0160458,WO0160369, WO0160368, WO0156552, WO0151494, WO0146138, WO0146137,WO0136395, WO0109127, WO0109125, WO0109124, WO0109112, WO0107437,WO0078363, WO0070083, WO0064891, WO0061145, WO0052134, WO0051612,WO0051611, WO0051547, WO0041992, WO0039716, WO0039119, WO0039082,WO0037459, WO0037458, WO0037076, WO0034239, WO0031064, WO0027803,WO0016778, WO0012543, WO0006748, WO0001691, WO0001678, WO0001674,WO0001411, WO0001386, WO9958132, WO9955725, WO9943314, WO9941235,WO9938862, WO9933834, WO9932114, WO9928315, WO9928314, WO9928313,WO9927933, WO9927929, WO9927928, WO9920612, WO9920611, WO9920609,WO9918951, WO9910525, WO9910524, WO9910523, WO9910329, WO9909985,WO9906580, WO9905117, WO9901434, WO9900654, WO9857970, WO9857968,WO9857965, WO9857963, WO9857962, WO9857961, WO9857960, WO9857959,WO9857955, WO9857950, WO9857949, WO9857948, WO9857947, WO9857946,WO9857945, WO9857944, WO9857654, WO9857633, WO9844797, WO9843629,WO9840383, WO9834921, WO9832741, WO9830558, WO9829390, WO9829119,WO9828980, WO9820001, WO9817629, WO9811106, WO9811100, WO9811099,WO9811098, WO9811097, WO9811096, WO9811093, WO9811092, WO9811091,WO9809641, WO9807692, WO9804545, WO9802436, WO9749700, WO9745412,WO9744350, WO9743437, WO9738665, WO9738664, WO9736901, WO9736900,WO9736898, WO9736897, WO9736896, WO9736892, WO9736891, WO9736890,WO9736889, WO9736888, WO9736886, WO9736881, WO9736879, WO9736877,WO9736876, WO9736875, WO9736605, WO9736593, WO9736592, WO9736591,WO9736587, WO9736585, WO9736584, WO9736583, WO9730992, WO9730053,WO9727854, WO9727853, WO9727852, WO9727752, WO9723478, WO9721701,WO9718813, WO9716443, WO9706138, WO9705902, WO9705270, WO9703050,WO9703047, WO9702817, WO9701275, WO9639137, WO9637204, WO9635707,WO9634010, WO9631525, WO9631501, WO9631477, WO9630343, WO9630015,WO9630014, WO9625512, WO9624612, WO9624611, WO9622278, WO9617861,WO9617623, WO9610037, WO9610035, WO9610034, WO9610011, WO9609836,WO9609821, WO9609820, WO9606609, WO9534535, WO9532191, WO9526981,WO9525092, WO9520396, WO9512612, WO9511917, WO9509001, WO9509000,WO9500497, WO9426723, WO9419357, WO9418157, WO9410184, WO9410138,WO9410137, WO9409766, WO9407485, WO9404561, WO9402134, WO9400419, andWO9116340. Particularly preferred are the farnesyl transferase inhibitorcompounds described in the following international patent applicationsand publications: WO00/39130, WO98/00409, WO99/65922, WO99/65898,WO99/64401, and PCT/US01/23959.

According to yet another preferred aspect, the present invention relatesto a drug combination comprising at least one anthracycline compound andat least one farnesyl transferase inhibitor compound, wherein saidanthracycline compound is described in one or more of the followingUnited States patents, the disclosure of each of which is herebyincorporated by reference in its entirety: U.S. Pat. Nos. 6,437,105,6,433,150, 6,403,563, 6,284,738, 6,284,737, 6,245,358, 6,194,422,6,187,758, 6,184,374, 6,184,365, 6,160,102, 6,107,285, 6,103,700,6,087,340, 6,080,396, 5,977,082, 5,965,407, 5,958,889, 5,948,896,5,945,518, 5,942,605, 5,843,903, 5,801,257, 5,789,386, 5,776,458,5,744,454, 5,719,130, 5,710,135, 5,593,970, 5,587,495, 5,532,218,5,294,701, 5,260,425, 5,242,901, 5,220,001, 5,212,291, 5,196,522,5,162,512, 5,124,318, 5,124,317, 5,122,368, 5,091,373, 5,091,372,5,045,534, 5,004,606, 5,003,055, 4,997,922, 4,965,352, 4,959,460,4,952,566, 4,950,738, 4,948,880, 4,946,831, 4,918,173, 4,918,172,4,914,191, 4,897,470, 4,870,058, 4,863,739, 4,855,414, 4,840,938,4,839,346, 4,833,241, 4,795,808, 4,772,688, 4,734,493, 4,713,371,4,710,564, 4,697,005, 4,675,311, 4,663,445, 4,642,335, 4,632,922,4,612,371, 4,591,636, 4,564,674, 4,563,444, 4,562,177, 4,550,159,4,537,882, 4,534,971, 4,526,960, 4,522,815, 4,474,945, 4,472,571,4,465,671, 4,439,603, 4,438,105, 4,424,342, 4,419,348, 4,411,834,4,409,391, 4,405,713, 4,405,522, 4,401,812, 4,393,052, 4,387,218,4,385,122, 4,383,037, 4,373,094, 4,366,149, 4,360,664, 4,355,026,4,351,937, 4,337,312, 4,327,029, 4,325,946, 4,322,412, 4,309,503,4,303,785, 4,293,546, 4,267,312, 4,264,510, 4,263,428, 4,259,476,4,247,545, 4,245,045, 4,244,880, 4,215,062, 4,209,588, 4,207,313,4,192,915, 4,166,848, 4,138,480, 4,134,903, 4,133,877, 4,127,714,4,067,969, and 3,963,760.

According to yet another preferred aspect, the present invention relatesto a drug combination comprising at least one anthracycline compound andat least one farnesyl transferase inhibitor compound, wherein saidanthracycline compound is described in one or more of the followingUnited States patent publications, the disclosure of each of which ishereby incorporated by reference in its entirety: 20020137694,20020077303, and 20010053845.

According to still yet another preferred aspect, the present inventionrelates to a drug combination comprising at least one anthracyclinecompound and at least one farnesyl transferase inhibitor compound,wherein said anthracycline compound is described in one or more of thefollowing international patent applications and publications, thedisclosure of each of which is hereby incorporated by reference in itsentirety: WO0187814, WO0164197, WO0076525, WO0066093, WO0056267,WO0044762, WO0027404, WO0026223, WO0015203, WO9966918, WO9958543,WO9957126, WO9952921, WO9948503, WO9945015, WO9935153, WO9931140,WO9929708, WO9908687, WO9846598, WO9840104, WO9839337, WO9802446,WO9749433, WO9749390, WO9740057, WO9733897, WO9729191, WO9719954,WO9712895, WO9700880, WO9639121, WO9629335, WO9607665, WO9524412,WO9516695, WO9516693, WO9509173, WO9426311, WO9420114, WO9405259,WO9313804, WO9305774, WO9216629, WO9210212, WO9207866, WO9119725,WO9105546, WO9010639, WO9004601, WO9001490, WO9000173, WO8911532,WO8809823, WO8809166, WO8703481, WO8203769 and WO8002112.

According to a more preferred aspect, the present invention relates todrug combinations comprising at least one farnesyl transferase inhibitorcompound described in International Patent Publication No. WO 00/39130with an anthracycline. Among the anthracyclines, doxorubicin,daunorubicin, epirubicin, idarubicin, and amrubicin are preferred, anddoxorubicin is most preferred. The disclosure of International PatentPublication No. WO 00/39130 is specifically incorporated herein byreference in its entirety.

In a particularly preferred embodiment the invention features a drugcombination comprising Compound A and doxorubicin.

As a result of their mechanism of action, the farnesyl transferaseinhibitor compounds, especially the compounds mentioned above, ingeneral have a cytostatic-type activity.

In employing the drug combinations according to the invention comprisingat least one farnesyl transferase inhibitor and at least oneanthracycline a goal is to obtain an increased anti-cancer activity,such as, for example, a prolonged stabilization of the size of thetumor, or a tumor regression.

According to the present invention, a composition is active if after itsadministration, it inhibits, retards or prevents the proliferation oftumor cells. Thus an advantageous characteristic of a pharmaceuticalcomposition comprising a drug combination according to the invention canbe an increase in the delay of tumor growth.

The drug combinations according to the present invention canadvantageously prolong or maintain the anticancer activity of either theanthracycline compound or the farnesyl transferase compound, incomparison with the activities obtained with each of the anthracyclinecompound or the farnesyl transferase compound considered in isolation.

A further advantage of the combinations according to the presentinvention relates to toxicity. Specifically, the therapeutic synergy ofthe combinations allows for lower dosages of one or both of thecomponents relative to the dosages that would be required to achieve thesame level of therapeutic activity if the components were administeredindividually.

The term “prodrug” refers to a pharmaceutically acceptable metabolicprecursor of a drug of interest; i.e., a compound or composition whichis converted to an active form of a desired drug in the body.

Certain abbreviations are used herein, as follows:

EBERs EBV-encoded RNAs

EBNA1 Epstein-Barr nuclear antigen 1

EBV Epstein-Barr virus

Ftase farnesyl-transferase

GGTase geranylgeranyl-transferase

FTI farnesyltransferase inhibitors

LMP1 latent membrane protein 1

NPC nasopharyngeal carcinoma

TRAF TNF-receptor associated factor

The anthracycline compound and the farnesyl transferase inhibitingcompound which form the drug combination of the invention can beadministered simultaneously, separately or sequenced over time, it beingpossible to adapt this frequency so as to obtain the maximum efficacy ofthe combination and, for each administration, to have a variableduration ranging from a rapid total administration to a continuousperfusion. The compounds which form the combination can be administeredat different rates, can be administered independently according toschemes chosen from the continuous, intermittent, repeated, alternatedor sequential schemes, and can be repeated a number of times per day.

Advantageously, the farnesyl transferase inhibitor having a cytostaticactivity can be administered according to a continuous scheme. Moreadvantageously, this scheme allows the plasma levels to be maintainedhigher than or equal to the concentration necessary to inhibit 50% ofthe growth of the cells (IC₅₀), e.g., as determined in the in-vitro cellviability assay described herein. Advantageously, the anthracycline canbe administered according to a scheme dependent on the type of tumormodel; preferably according to an intermittent scheme.

It follows from the foregoing that the drug combinations of the presentinvention are not limited to those which are obtained by physicalassociation of the constituents, but also to those which allow aseparate administration which can be simultaneous or spread out overtime. Thus the constituents can be administered independently accordingto distinct methods and routes including, without limitation, the oral,intraperitoneal, parenteral, intravenous, topical, rectal, vaginal, andrespiratory mucosa routes.

Advantageously, the farnesyl transferase inhibitor and anthracyclineconstituents of the combinations according to the invention areadministered orally; most preferably, the farnesyl transferase inhibitorand anthracycline constituents of the drug combinations according to theinvention are bioavailable by the oral route.

Also advantageously, the farnesyl transferase inhibitor andanthracycline constituents of the drug combinations according to theinvention may be administered intravenously.

Also advantageously, the farnesyl transferase inhibitor constituents maybe administered orally and the anthracycline constituents may beadministered intravenously, or vice versa.

The products for intravenous injection are generally pharmaceuticallyacceptable sterile solutions or suspensions which optionally can beprepared extemporaneously at the time of use. For the preparation ofnon-aqueous solutions or suspensions, natural vegetable oils can be usedsuch as olive oil, sesame oil or paraffin oil or injectable organicesters such as ethyl oleate. The sterile aqueous solutions can be formedof a solution of one or both of the anthracycline compound and thefarnesyl transferase inhibiting compound in water. The aqueous solutionsare suitable for intravenous administration inasmuch as the pH issuitably adjusted and the isotonicity is produced, for example, by asufficient quantity of sodium chloride or of glucose. Sterilization canbe carried out by heating or by any other means which does not adverselyaffect the composition. The drug combinations can also be present in theform of liposomes or in combination form with supports such ascyclodextrins or polyethylene glycol's.

As solid compositions for oral administration, compressed tablets,pills, powders (gelatin capsules, cachets) or granules can be used. Inthese compositions, one or both of the anthracycline compound and thefarnesyl transferase inhibiting compound is mixed with one or more inertdiluents, such as starch, cellulose, sucrose, lactose or silica, under acurrent of argon. These compositions can likewise comprise substancesother than the diluents, for example one or more lubricants such asmagnesium stearate or talc, a colorant, a coating (coated tablets) or alacquer.

As liquid compositions for oral administration, it is possible to usepharmaceutically acceptable solutions, suspensions, emulsions, syrupsand elixirs comprising inert diluents such as water, ethanol, glycerol,vegetable oils or paraffin oil. These compositions can comprisesubstances other than the diluents, for example wetting, sweetening,thickening, flavoring or stabilising products.

The compositions for rectal administration are suppositories or rectalcapsules which contain, apart from one or both of the anthracyclinecompound and the farnesyl transferase inhibiting compound, excipientssuch as cocoa butter, semi-synthetic glycerides or polyethylene glycols.The compositions for topical administration can be, for example, creams,lotions, eye lotions, mouthwashes nasal drops or aerosols.

Generally speaking, the physician will determine the appropriate dosageof each of the anthracycline compound and the farnesyl transferaseinhibiting compound as a function of the age, weight and all the otherfactors individual to the subject to be treated. Generally the dosesdepend on the effect sought, the duration of the treatment and the routeof administration used. Doses generally range, as far as the farnesyltransferase inhibitor is concerned, from 10 mg to 2000 mg per day by theoral route for an adult with unit doses ranging from 50 mg to 1000 mg ofactive substance; and as far as the anthracyclines are concerned: from10 mg to 1000 mg of active substance per day by the intravenous routefor an adult. The treatment can be repeated a number of times per day orper week as determined appropriate by the physician. Preferably thetreatment is continued until a stabilisation, a partial remission, atotal remission or a recovery is achieved.

In the combinations according to the invention for which theadministration of the constituents can be simultaneous, separated orspread out over time, it is particularly advantageous that the quantityof the farnesyl transferase inhibitor compound is from 10 to 90% byweight of the combination, it being possible for this content to vary asa function of the nature of the associated substance, the efficacysought and the nature of the cancer cells to be treated.

The drug combinations according to the invention can be utilized for thetreatment of diseases connected with malignant or benign cellproliferations of the cells of various tissues and/or organs, comprisingthe muscle, bone or connective tissues, the skin, the brain, the lungs,the sex organs, the lymphatic or renal systems, the mammary or bloodcells, the liver, the digestive apparatus, the colon, the pancreas andthe thyroid or adrenal glands, and including the following pathologies:psoriasis, restenosis, different types of sarcomas such as Kaposi'ssarcoma, cancers of the head and of the neck, the pancreas, the colon,the lung, the ovary, the breast, the brain, the prostate, the liver, thestomach, the bladder, the kidney, the prostate or the testicles, Wilm'stumor, teratocarcinomas, cholangiocarcinoma, choriocarcinoma, melanomas,cerebral tumors such as neuroblastoma, gliomas, multiple myelomas,leukemias and lymphomas such as chronic lymphocytic leukemias, acute orchronic granulocytic lymphomas, and Hodgkin's disease.

The combinations according to the invention can be particularly usefulfor the treatment of cancers such as cancers of the pancreas, the colon,the lung, the ovary, the breast, the brain, the prostate, the liver, thestomach, the bladder or the testicles, and of the head and neck, andmore advantageously cancer of the head and neck. In a particularlypreferred embodiment of the invention a combination according to theinvention is used for the treatment of nasopharyngeal carcinoma.

In particular, the drug combinations of the invention have the advantageof being able to employ the anthracycline compound and/or the farnesyltransferase inhibiting compound in doses which are lower than those inwhich either compound is used alone.

Thus the present invention relates to the use of combinations comprisingat least one farnesyl transferase inhibitor and at least oneanthracycline for the preparation of medicaments useful for thetreatment of the above mentioned pathologies; advantageously cancers,most advantageously nasopharyngeal carcinoma. Further the presentinvention relates to the use of drug combinations comprising at leastone farnesyl transferase inhibitor and at least one anthracycline forthe preparation of medicaments for administration which is simultaneous,separate or sequenced over time.

The farnesyl transferase inhibitor compounds referenced herein can beprepared by means commonly known to those skilled in the art, asevidenced by the patents already specifically incorporated by referenceherein. Likewise the anthracycline compounds can be prepared by meanswell-known in the art.

The present invention is further illustrated by the following exampleswhich are designed to teach those of ordinary skill in the art how topractice the invention. The following examples are merely illustrativeof the invention and should not be construed as limiting the inventionas claimed.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Detection of the EBERs in NPC tumor lines and assessment of NPCcell proliferation in vitro. A and B: in situ hybridization of the EBERson tissue sections of xenografted tumors formed by C15 (A) and C666-1(B) NPC cells. (scale bar: 20 μM). C: Ki 67 immunostaining of C15 cellsgrown in vitro for 72 h on PolyHema matrix; cell aggregates (averagesize 150 μM) were cytospined and fixed in acetone (10 min/4° C.) priorto immunostaining (scale bar: 10 elm). D: Proliferation of C15 (solidline) and C666-1 (dotted line) cells in vitro demonstrated by sequentialWST-1 assays. Cells were seeded in 96 well plates at 10⁵/well on plasticcoated with PolyHema (C15) and 35×10³/well without plastic coating(C666-1). The WST-1 reaction was performed at 24, 48 and 72 hours toassess the evolution of cell viability reflected by absorbance at 490nm. Data are the means (±standard deviation) of quadruplicates. Similarresults were obtained in three separate experiments.

FIG. 2. Effect of Compound A, alone or in combination with doxorubicin,on NPC cell viability. C15 and C666-1 cells were grown in 96 wellplates, in the presence of various concentrations of pharmacologicalagents, prior to assessment of cell viability using the WST-1 assay. Theobserved results are reported as means (±standard deviation) ofquadruplicates and are representative of three similar experiments. A:treament of NPC cells with various concentrations of Compound A alone.B: treament of NPC cells with various concentrations of doxorubicin withor without Compound A, 5 μM (C15) or 10 μM (C666-1).

FIG. 3. Induction of nuclear fragmentation in C15 cells treated bydoxorubicin combined to Compound A. Nuclei were visualized by Hoechst33342 staining (scale bar: 10 μm). A: non-treated cells. B: cellstreated for 48 hrs with doxorubicin (1 μM) combined to Compound A (5μM); most nuclei shrank (arrows) and exhibited chromatin condensationand fragmentation (arrowheads).

FIG. 4. Induction of caspase activation in C15 cells treated bydoxorubicin combined to Compound A. C15 cells were treated withdoxorubicin (1 μM), Compound A (5 μM) or a combination of both moleculesfor 48 h. Measurement of caspase activation was based on selectiveintra-cellular retention of a fluorescent caspase substrate inhibitor(VAD-fluoromethyl ketone labelled with carboxyfluorescein). Retention ofthe fluorescent substrate was assessed by flow cytometry in non-treated(grey line) or treated (black line) C15 cells.

FIG. 5. Induction of PARP-cleavage in C15 cells treated by doxorubicincombined to Compound A. C15 cells were treated with doxorubicin (1 μM),Compound A (5 μM) or a combination of both for the indicated periods.Corresponding cell lysates (50 μg protein per lane) were separated by7.5% SDS-PAGE and analyzed by Western Blot with an anti-PARP monoclonalantibody. The cleaved product of PARP was at 85 kD, as shown in thepositive-control extract derived from C15 cells treated with the CD95agonist-antibody 7C11.

FIG. 6. Induction of TRAF1-cleavage in C15 cells treated withdoxorubicin combined to Compound A. A: Diagram of Fas-mediatedTRAF-1-cleavage as reported by Leo et al. (2001). The locations oftarget peptides used for production of the H-3 monoclonal and H-132polyclonal antibody are indicated by hatched boxes. The peptide targetedby H-3 was entirely contained in fragment II whereas the peptidetargeted by H132 was mainly co-linear with fragment I. B: C15 cells weretreated for 24 h with doxorubicin (1 μM), Compound A (5M) or acombination of both. Control cells were treated with the Fas-agonistantibody 7C11. Cell lysates (50 μg protein per lane) were separated on a8-16% SDS-PAGE linear gradient prior to Western Blot analysis withanti-TRAF-1 antibodies. Both antibodies detected a main band at 46 kdAdditional bands corresponding to fragments of smaller sizes werevisible, mainly in samples treated with 7C11 or the combination ofdoxorubicin and Compound A. In the extracts of cells treated with 7C11,these smaller fragments had apparent molecular weights of 29 kD (H-3)and 24 kD (H-132) which were compatible with the sizes of TRAF1fragments reported by Leo et al. (2001). Similar results were obtainedin three similar experiments.

DETAILED DESCRIPTION OF THE INVENTION

Materials

Compound A and BIM-46068 were provided by Biomeasure, Incorporated(Milford, Mass.). FTI-277 and GGTI-286 were provided by Expansia(Aramon, France). Taxol, cis-platin, doxorubicin and 5-fluorouracyl werepurchased from Sigma (Saint-Quentin Fallavier, France). C15 is anundifferentiated NPC tumor line propagated by sub-cutaneous passage intonude mice. (Busson, P., et al., Establishment and characterization ofthree transplantable EBV-containing nasopharyngeal carcinomas. Int JCancer, 42: 599-606, 88.) It was established from the biopsy of aprimary nasopharyngeal tumor in a 13-year-old girl born in Morocco. Thebiopsy was collected prior to any therapeutic procedure, according tothe institutional guidelines concerning the use of clinical material.This patient had a voluminous primary tumor associated with lymph nodeand bone metastases and was treated by induction chemotherapy with acombination of vincristine, cyclophosphamide, doxorubicin andmethylprednisolone, prior to nasopharyngeal and cervical radiotherapy. A70% tumor response was achieved in both the primary tumor and cervicallymph node metastases after two months of chemotherapy. Completeclinical remission was obtained after radiotherapy, however remissionlasted only 5 months, due to recurrence of bone metastases. C15 cellsexpress a wild type p53 protein. (Effert, P., et al., Alterations of thep53 gene in nasopharyngeal carcinoma. J Virol, 66: 3768-3775, 1992.)C666-1 is an EBV-positive NPC cell line propagated in vitro related toan NPC xenograft, called xeno-666. (Cheung, S. T., et al.,Nasopharyngeal carcinoma cell line (C666-1) consistently harbouringEpstein-Barr virus. Int J Cancer, 83: 121-126, 1999.) A primary in vitroculture was derived from xeno-666 at passage 18 and named C666.Subsequently, C666 was adapted to low density growth and severalsub-clones were isolated. One of them, named C666-1, was extensivelycharacterized and later used in this study. (Id.; Weinrib, L., et al.,Cisplatin chemotherapy plus adenoviral p53 gene therapy in EBV-positiveand -negative nasopharyngeal carcinoma. Cancer Gene Ther, 8: 352-360.,2001.) C666-1 cells express a mutated p53 protein. (Weinrib, L., et al.,Cancer Gene Ther, 8: 352-360., 2001.) In situ hybridization of EBER's(EBV-encoded RNA's).

Pieces of xenografted C15 and C666-1 tumors were fixed (in a mix ofacetic acid, formaldehyde and ethanol), paraffin-embedded and cut in 4μm sections. EBER's detection was performed by in situ hybridizationwith a mixture of peptide nucleic acid (PNA) probes reacting with bothEBER 1 and 2 and labelled with fluorescein (Dako EBER-PNA probe, Dako,Trappes, France). The hybridization process was done as recommended bythe manufacturer, using RNA's-free water. Hybridized probes weredetected with anti-fluorescein antibodies conjugated to alcalinephosphatase (PNA ISH detection kit, Dako).

Preparation of NPC Cells for In Vitro Experiments.

Prior to in vitro experiments, C15 xenografted tumors were minced andtreated with type II collagenase for cell dispersion, as previouslyreported. (Sbih-Lammali, F., et al., Control of apoptosis in EpsteinBarr virus-positive nasopharyngeal carcinoma cells: opposite effects ofCD95 and CD40 stimulation. Cancer Res, 59: 924-930, 1999.) Residual cellaggregates were removed by filtration on a nylon cell strainer with 100μm pores. C666-1 cells were permanently propagated in vitro in plasticflasks coated with collagene I (Biocoat, Becton-Dickinson, France). Invitro culture medium was Hepes-buffered RPMI with 5% fetal calf serumfor both C15 and C666-1 cells. C666-1 cells which were derived from asingle malignant clone were free of contaminating murine fibroblasts. Incontrast, C15 cell suspensions were often contaminated by murinefibroblasts. Therefore, for some experiments, C15 cell suspensions weregrown on plastic coated with Poly(2-HydroxyEthylMethacrylate), ananti-adhesive polymer which inhibits cell attachment, (Fukazawa, H., etal., Inhibitors of anchorage-independent growth affect the growth oftransformed cells on poly(2-hydroxyethyl methacrylate)-coated surfaces.Int J Cancer, 67: 876-882, 1996.), (PolyHEMA, Sigma, Saint-QuentinFallavier, France). Using this coating procedure, fibroblastproliferation was completely inhibited whereas C15 cells grew asnon-anchored spheroids or aggregates of 150 μm average diameter at 72 h(FIG. 1). Ki 67 immunostaining.

C15 cell aggregates were deposited on glass slides by cytospinning,fixed in acetone at 4° C. for 10 min and stained with a mouse monoclonalantibody against the KI 67 antigen (Dako, Trappes, France). Thisantibody is specific of the human antigen and does not cross-react withits murine counter-part. Immunoreactivity was detected with peroxidaseconjugated antibodies (Power vision kit, ImmunoVision technologies, DalyCity, Calif.). Slides were counterstained with hematoxylin. In vitroprenyl-transferase assays.

The effect of Compound A and other drugs on FTase activity was assayedin vitro with FTase from human brain cytosol (ABS Reagents, Wilmington,Del.) as target enzyme and recombinant human H-Ras protein containingthe wild type CAAX box (Biomol, Plymouth Meeting, Pa.) as a specificsubstrate. The incubation mixture (25 μl) for [³H]-farnesylationcontained 50 mM Tris-HCl (pH 7.5), 5 mM dithiothreitol, 20 μM ZnCl₂, 40mM MgCl₂, 0.6 μM [³H]-farnesyl pyrophosphate (22.3 Ci/mmol) (NEN,Boston, Mass.), 4 μM recombinant H-Ras and 10 μg FTase. After 60 min at37° C., the reaction was stopped by adding 150 μl of absolute ethanol.The mixture was then filtered on Unifilter GF/B microplate (Packard,Rungis, France) and washed 6 times with ethanol prior to scintillationcounting. After adding 50 μl of Microscint 0, plates were counted with aPackard Top Count scintillation counter. Drug effects on GGTase Iactivity were assayed by a similar method with GGTase I from human brain(ABS reagent) as target enzyme and human recombinant H-Ras containing amutated CAAX box (CVLL)(Biomol). The incubation mixture contained 4 μMrecombinant H-Ras, 0.6 μM [³H]-geranylgeranyl-pyrophosphate (19.3Ci/mmol) (NEN) and 100 μg of GGTase I. GGTI-286 was used as a positivecontrol for the GGTase-I inhibition assay. Results were expressed as theconcentrations of drugs required to inhibit 50% of prenyl-incorporationinto the recombinant H-Ras proteins (IC₅₀). Assessment offarnesyl-transferase inhibition in intact cells.

The effect of Compound A on farnesyl-transferase in intact cells wasassayed in MIAPaca cells, a human pancreatic carcinoma cell line whichwas purchased from the ATCC. Both H-Ras and N-Ras were investigated asreference substrates of the endogenous farnesyl-transferase. Totalprotein extracts were prepared from MIAPaca cells treated for 48 h withincreasing concentrations of Compound A (1-100 nM) along with extractsfrom untreated cells as a negative control. A positive control wasprovided by cells treated with mevastatine (30 μM). Mevastatine is anHMG-CoA reductase inhibitor which blocks the synthesis of farnesylmetabolic precursors. Cell extracts were separated by SDS-polyacrylamidegels (15%) and analyzed by Western blot with polyclonal antibodiesdirected to H-Ras and N-Ras (Santa Cruz, Heidelberg, Germany).Farnesyl-transferase inhibition was assessed indirectly by detection ofnon-prenylated forms of H-Ras and N-Ras which were slightly shiftedtoward higher molecular weights and reacted more efficiently withantibodies. Assessment of drug effect on NPC cell viability.

Cell viability assays were performed in 96 well plastic microplates,either uncoated (C666-1) or coated with Poly HEMA (C15). For each cellline, the number of cells distributed per well was optimized in order toachieve the highest metabolic activity while keeping exponential growthtill the end of the test. C15 and C666-1 cells were seeded at 10⁵ and35×10³/well, respectively, in 150 μl culture medium. Following anovernight pre-incubation culture, serial dilutions of chemotherapy drugs(50 μl; final concentration 50 nM-50 μM) were added in quadruplicate toa final volume of 250 μl. At the completion of a 72 h incubation withtested pharmacological agents, cell viability was evaluated using theWST-1 assay (Roche Molecular, France). The WST-1 assay is based on thecleavage of the tetrazolium salt by mitochondrial dehydrogenases. Incontrast with other tests, it does not require washing the cells inmicroplate wells and is compatible with spheroid culture. Cells wereincubated with 10 μl of the WST-1 reagent added to the culture medium,for 3 to 6 h, at 37° C. The plates were subsequently read on an ELISAreader (Dynatech MR7000, Guernsey channel Island, USA) using a 490 nmfilter. The mean and standard deviation were determined forquadruplicate samples. For each compound, values falling in the linearpart of sigmoid curve were included in a linear regression analysis andwere used to estimate the 50% inhibitory concentration (IC 50).Measurement of caspase activity in drug treated NPC cells.

Caspase activity was assessed at single cell level by flow cytometryusing the CaspaTag kit according to manufacturer instructions(Quantum-Appligene, Illkirch, France). This procedure involved acell-permeable, general caspase inhibitor (VAD-fluoromethyl ketone)labelled with carboxyfluorescein. This fluorescent inhibitorirreversibly binds to active caspases and therefore is selectivelyretained in apoptotic cells. For apoptosis induction, C15 and C666-1cells were seeded in 24 well plates at 10⁶ and 3×10⁵ cells/wellrespectively, pre-incubated overnight and treated with drugs for 48 h.In this context, it was not possible to incubate C15 cells on PolyHEMA,because the resulting cell aggregates were not suitable for flowcytometry. In order to discriminate human malignant cells fromcontaminating murine fibroblasts, C15 cell suspensions were submitted toadditional staining with an anti-human HLA (human leukocyte antigen) A,B, C directly conjugated to allo-Phyco-Cyanine (Becton Dickinson,Meylan, France). In a first step, both C15 and C666-1 cells wereincubated for 1 h at 37° C., in their culture plates, with fluorescentVAD-FMK, in 300 μl of culture medium. Cells were then washed andtrypsinized. C15 cells were further incubated with the anti-HLAantibody. Finally, both caspase and HLA fluorescence were analysed usinga FACS calibur flow cytometer (Becton Dickinson, Franklin Lakes, N.J.).

Assessment of PARP (Poly(ADP-ribose)polymerase) and TRAF1 cleavage.

Whole cell extracts were prepared from drug-treated and control C15 andC666-1 cells in RIPA-SDS buffer. (Sbih-Lammali, F., et al., Control ofapoptosis in Epstein Barr virus-positive nasopharyngeal carcinoma cells:opposite effects of CD95 and CD40 stimulation. Cancer Res, 59:924-930,1999.) Thirty to fifty μg of total protein extract were submitted toelectrophoresis on 7.5% (PARP) or 8-16% gradient (TRAF1)SDS-polyacrylamide gels. Separated proteins were transferred toImmobilon membranes (Millipore, France) which were probed with anti-PARP(Oncogene, Boston, Mass.) or anti-TRAF-1 (Santa Cruz, Heidelberg,Germany) antibodies revealed with horseradish peroxidase-conjugatedantibodies (Amersham, Les Ulis, France). Detection was performed withthe ECL chemiluminescence system (Amersham, Les Ulis, France). Two typesof antibodies from Santa Cruz were used for study of TRAF1-cleavage: themonoclonal H-3 and the H-132 polyclonal; a positive control was providedby C15 cells treated for 24 h with the CD95-agonist antibody, 7C11(Immmunotech, Marseille, France).

Detection of EBER's in NPC Tumor Lines.

In order to check that both C15 and C666-1 retained latentEBV-infection, EBER's expression was detected by in situ hybridizationin both tumor lines (FIG. 1 A and B) (C666-1 xenografted tumors werereformed by cell injection into nude mice at in vitro passage 40). Asexpected, EBER's staining was essentially nuclear. Most but not allmalignant cells were positively stained, an observation which isconsistent with previous reports about fresh NPC biopsies. (Wu, T. C.,et al., Abundant expression of EBER1 small nuclear RNA in nasopharyngealcarcinoma. A morphologically distinctive target for detection ofEpstein-Barr virus in formalin-fixed paraffin-embedded carcinomaspecimens. Am J Pathol, 138: 1461-1469, 1991.) Assessment of C15 andC666-1 proliferation.

As previously reported, C666-1 cells consistently proliferated in vitro,growing as cell monolayers in various types of plastic vessels. (Cheung,S. T., et al., Nasopharyngeal carcinoma cell line (C666-1) consistentlyharbouring Epstein-Barr virus. Int J Cancer, 83: 121-126, 1999.) Inorder to prevent increasing contamination by murine fibroblasts,tumor-dispersed C15 cells were seeded in microplates coated withPolyHema matrix and grown as floating aggregates. These aggregated cellsremained proliferating as demonstrated by immuno-cytological detectionof the human Ki-67 antigen in a significant fraction of them (FIG. 1C).In addition, repeated measurements of WST reduction during 3 consecutivedays of culture demonstrated a consistent, steady increase of viablecells (FIG. 1D). C15 cell doubling time was estimated at 1.5 days. Inthe same plates, without plastic coating, the doubling time of C666-1cells was about 3.5 days (FIG. 1D).

Short Term Cytotoxicity of Conventional Drugs Applied on NPC Cells InVitro.

Cis-platinum, bleomycine, 5FU, doxorubicine and taxol are among thedrugs most frequently used in chemotherapy of NPC. (Ali, H. et al.,Chemotherapy in advanced nasopharyngeal cancer. Oncology (Huntingt),14:1223-1230, 2000.) Their short term cytotoxic effect was assessed invitro on the C15 and C666-1 cells, using a cell viability assay based onWST reduction. Cultured cells were incubated in the presence of variousconcentrations of each therapeutic agent for 72 hours. As shown Table I,both C15 and C666-1 were highly sensitive to doxorubicin atconcentrations of below 1 μM. C666-1 cells were also highly sensitive totaxol, whereas C15 cells were totally resistant to this drug. On theother hand, C15 was mildly sensitive to the cytotoxic effect ofcis-platinum (1 μM IC₅₀) whereas C666-1 cells were five times moreresistant. No significant effects of bleomycin or 5-FU were observed ineither cell line at the concentrations tested.

Characterization of a Farnesyl-Transferase Inhibitor

Although doxorubicin was very active on both C15 and C666-1, it was notobserved to induce massive apoptosis in these cell lines at theconcentrations tested. Therefore it was postulated to use molecularlytargeted agents, especially farnesyl-transferase inhibitors (FTI's) incombination with doxorubicin, to increase its cytotoxic effect andattempt to induce apoptosis. Compound A is a peptidomimetic FTI whichhad been designed to be highly selective of farnesyl-transferase. Thebiological activity of this compound was first assayed for its effect onthe activity of purified human prenyl-transferase and its inhibition ofras-processing in intact cells. Table II shows that Compound A is apotent inhibitor of human brain FTase in vitro. The IC₅₀ value is in thenanomolar range and compares favourably with the tested known FTIcompounds FTI-277 and BIM-46068. (Sun, J., et al., Ras CAAXpeptidomimetic FTI 276 selectively blocks tumor growth in nude mice of ahuman lung carcinoma with K-Ras mutation and p53 deletion. Cancer Res,55: 4243-4247, 1995; Prevost, G. P., et al., Inhibition of human tumorcell growth in vitro and in vivo by a specific inhibitor of humanfarnesyltransferase: BIM-46068. Int J Cancer, 83: 283-287, 1999.) It isnoteworthy that in contrast to other tested FTI's, no activity onGGTase-I by Compound A was observed at concentrations of up to 100 μMthus showing its high selectivity for FTase. The effect of Compound A onprotein-farnesylation was further assessed in intact MIAPaca cells whichare prototype target cells for prenylation-inhibitors. H-Ras and N-Ras,which are classical substrates for farnesyl-transferases, are bothexpressed and non-mutated in MIAPaca cells. A significant inhibition ofH-Ras and N-Ras farnesylation was obtained when cells were incubatedwith only 50 nM of Compound A for 48 h.

Enhancement of Doxorubicin Cytotoxic Activity on NPC Cells when Used inCombination with Compound A.

As shown in FIG. 2A, Compound A had only limited toxicity on both C15and C666-1 cells when it was used alone (IC₅₀=10 μM). However, thecytotoxic effect of doxorubicin was dramatically enhanced when it wascombined with Compound A. For C15 cells, a more than additive effect wasobvious for doxorubicin concentrations of 500 nM or 1 μM with Compound Aat 5 μM. For C666-1 cells a higher concentration of the FTI drug wasrequired to obtain a synergistic effect with doxorubicin. Still, a morethan additive effect was observed for doxorubicin concentrations of 1and 2 μM. In contrast, enhanced cisplatin and bleomycin cytotoxicity wasnot observed by combination with Compound A at test concentrations.

Contribution of Apoptosis to the Cytotoxic Effect of theDoxorubicin/Compound A Combination.

After 48 h incubation with the doxorubicin/Compound A combination, manyC15 cells started to round up, retract their processes, and subsequentlydetach from culture dishes. Under nuclear staining with Hoechst 33342,typical changes related to nuclear apoptosis—nuclear condensation andfragmentation—were detected at 48 h of incubation and became moreobvious after 72 h. Such morphological changes were much less apparentin C15 cells treated with doxorubicin or Compound A alone. In contrastto C15 cells, significant changes in the morphology of the nucleus werenot observed in C666-1 cells, even in the presence of both doxorubicinand Compound A, although some nuclei with partial chromatin condensationwere recorded. Apoptosis of C15 cells under treatment by both drugs wasfurther demonstrated by flow cytometry analysis of caspase activationwhich was obvious after a 48 h period of treatment. Finally PARPcleavage was analysed by Western blot in protein extracts of C15 cellstreated by one drug or the association of both. A strong PARP cleavagewas apparent after only a 24 h period of combined treatment. At 48 h,the intact fragment of the PARP was almost undetectable. Moderate PARPcleavage was also detected in cells treated by doxorubicin or Compound Aalone, but a much lower fraction of the protein was affected in theseexperimental conditions. No caspase-activation and PARP cleavage weredetected in C666-1 cells even when treated by doxorubicin combined withCompound A.

Cleavage of TRAF1 in C15 Cells Treated by the Compound A-DoxorubicinCombination.

NPC cells treated by doxorubicin and/or Compound A were investigated forTRAF1-cleavage. TRAF1 is a signalling adapter which has a restrictedtissue distribution but whose expression is ectopically induced byEBV-infection. (Mosialos, G., et al., The Epstein-Barr virustransforming protein LMP1 engages signaling proteins for the tumornecrosis factor receptor family. Cell, 80: 389-399, 1995.) It has beenreported that TRAF1 is strongly expressed by EBV-positive NPC cells.(Ardila-Osorio, H., et al., Evidence of LMP1-TRAF3 interactions inglycosphingolipid-rich complexes of lymphoblastoid and nasopharyngealcarcinoma cells. Int J Cancer, 81: 645-649, 1999.) On the other hand,Leo et al. (2001) have reported that TRAF1 is cleaved at aspartate 163in cells undergoing apoptosis, especially death receptor-mediatedapoptosis but also doxorubicin-induced apoptosis. (Leo, E., et al.,TRAF1 is a substrate of caspases activated during tumor necrosis factorreceptor-αinduced apoptosis. J Biol Chem, 55: 8087-8093, 2000) C15 cellstreated by a CD95-agonist (7C11) for 24 h were used as a positivecontrol; a dramatic decrease in the amount of intact TRAF1 was observedin the corresponding protein extracts. Simultaneously, there was amarked increase of the cleaved fragments characterised by Leo et al.,(Id.): fragment I (24 kD, reacting with the H-132 antibody) and II (30kD, reacting with H-3). In cells treated with doxorubicin or Compound Aalone, no modifications of the TRAF1 molecule were observed. Incontrast, a substantial increase of cleaved fragments similar tofragments I and II were observed in the extracts of cells treated by thecombination of doxorubicin and Compound A. There were some differencesin the patterns of cleavage induced by the CD95-agonist and the drugcombination. Despite the visualisation of cleaved fragments, the amountof intact TRAF1 molecule was only marginally reduced in drug-treatedcells. Further the cleaved fragment II consistently had a slightlybigger size than with the 7C11 agonist. TRAF1 was also detected inC666-1 cells and, although readily cleaved under treatment by theCD95-agonist, it was not cleaved under drug-treatment. This observationis consistent with the absence of apoptotic process.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Also, all publications, patentapplications, patents and other references mentioned herein areincorporated by reference.

It is to be understood that while the invention has been described inconjunction with the detailed description thereof, that the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. TABLE IEffects of conventional drugs on NPC cell viability in vitro.Determination of the IC 50. C15 Cells C666-1 Cells Doxorubicin 150 nM200 nM Cis-platinum 1 μM 5 μM Bleomycin 5 μM 5 μM 5-fluorouracyl 5 μM 5μM Taxol 25 μM 200 nMData are the mean of quadruplicates. Similar results were obtained inthree separate experiments.

TABLE II Comparative assessment of FTase inhibitor action on purifiedhuman prenyl transferase activities. Enzyme assays IC₅₀ (nM) FTaseGGTase I BIM-46068 91 (83-99) 268000 (15200-384000) FTI-277 30 (26-34)314 (305-323)  GGTI-286  365 (329-401) 114 (106-123)  Compound A 15(13-15) >100 μMAssay results are reported as the mean of 2 experiments with the lowestand highest IC₅₀ values observed in individual experiments inparentheses.

1. A pharmaceutical composition comprising a farnesyl transferaseinhibitor, a prodrug thereof or a pharmaceutically acceptable salt ofsaid farnesyl transferase inhibitor or of said farnesyl transferaseinhibitor prodrug, and an anthracycline, a prodrug thereof or apharmaceutically acceptable salt of said anthracycline or of saidanthracycline prodrug.
 2. A pharmaceutical composition according toclaim 1, wherein said farnesyl transferase inhibitor is according toformula I:

wherein n1 is 0 or 1; X is, independently for each occurrence,(CHR¹¹)_(n3)(CH₂)_(n4)Z(CH₂)_(n5); Z is O, N(R¹²), S, or a bond; n3 is,independently for each occurrence, 0 or 1; n4 and n5 each is,independently for each occurrence, 0, 1, 2, or 3; Y is, independentlyfor each occurrence, CO, CH₂, CS, or a bond;

or N(R²⁴ R²); R¹, R¹¹, and R¹² each is, independently for eachoccurrence, H or an optionally substituted moiety selected from thegroup consisting of (C₁₋₆)alkyl and aryl, wherein said optionallysubstituted moiety is optionally substituted with one or more of R⁸ orR³⁰; R³ is, independently for each occurrence, H or an optionallysubstituted moiety selected from the group consisting of (C₁₋₆)alkyl,(C₂₋₆)alkenyl, (C₂₋₆)alkynyl, (C₃₋₆)cycloalkyl,(C₃₋₆)cycloalkyl(C₁₋₆)alkyl, (C₅₋₇)cycloalkenyl,(C₅₋₇)cycloalkenyl(C₁₋₆)alkyl, aryl, aryl(C₁₋₆)alkyl, heterocyclyl, andheterocyclyl(C₁₋₆)alkyl, wherein said optionally substituted moiety isoptionally substituted with one or more R³⁰; R⁴ and R⁵ each is,independently for each occurrence, H or an optionally substituted moietyselected from the group consisting of (C₁₋₆)alkyl, (C₃₋₆)cycloalkyl,aryl, and heterocyclyl, wherein said optionally substituted moiety isoptionally substituted with one or more R³⁰, wherein each saidsubstituent is independently selected, or R⁴ and R⁵ can be takentogether with the carbons to which they are attached to form aryl; R⁶is, independently for each occurrence, H or an optionally substitutedmoiety selected from the group consisting of (C₁₋₆)alkyl, (C₂₋₆)alkenyl,(C₃₋₆)cycloalkyl, (C₃₋₆)cycloalkyl(C₁₋₆)alkyl, (C₅₋₇)cycloalkenyl,(C₅₋₇)cycloalkenyl(C₁₋₆)alkyl, aryl, aryl(C₁₋₆)alkyl, heterocyclyl, andheterocyclyl(C₁₋₆)alkyl, wherein said optionally substituted moiety isoptionally substituted with one or more substituents each independentlyselected from the group consisting of OH, (C₁₋₆)alkyl, (C₁₋₆)alkoxy,—N(R⁸R⁹), —COOH, —CON(R⁸R⁹), and halo, where R⁸ and R⁹ each is,independently for each occurrence, H, (C₁₋₆)alkyl, (C₂₋₆)alkenyl,(C₂₋₆)alkynyl, aryl, or aryl(C₁₋₆)alkyl; R⁷ is, independently for eachoccurrence, H, ═O, ═S, or an optionally substituted moiety selected fromthe group consisting of (C₁₋₆)alkyl, (C₂₋₆)alkenyl, (C₃₋₆)cycloalkyl,(C₃₋₆)cycloalkyl(C₁₋₆)alkyl, (C₅₋₇)cycloalkenyl,(C₅₋₇)cycloalkenyl(C₁₋₆)alkyl, aryl, aryl(C₁₋₆)alkyl, heterocyclyl, andheterocyclyl(C₁₋₆)alkyl, wherein said optionally substituted moiety isoptionally substituted with one or more substituents each independentlyselected from the group consisting of OH, (C₁₋₆)alkyl, (C₁₋₆)alkoxy,—N(R⁸R⁹), —COOH, —CON(R⁸R⁹), and halo; R¹⁰ is C; or when n1=0, R⁶ and R⁷can be taken together with the carbon atoms to which they are attachedto form aryl or cyclohexyl; R²¹ is, independently for each occurrence, Hor an optionally substituted moiety selected from the group consistingof (C₁₋₆)alkyl and aryl(C₁₋₆)alkyl, wherein said optionally substitutedmoiety is optionally substituted with one or more substituents eachindependently selected from the group consisting of R¹ and R³⁰; R²² isH, (C₁₋₆)alkylthio, (C₃₋₆)cycloalkylthio, R⁸—CO—, or a substituentaccording to the formula

R²⁴ and R²⁵ each is, independently for each occurrence, H, (C₁₋₆)alkyl,or aryl(C₁₋₆)alkyl; R³⁰ is, independently for each occurrence,(C₁₋₆)alkyl, —O—R⁸, —S(O)_(n6)R⁸, —S(O)_(n7)N(R⁸R⁹), —N(R⁸R⁹), —CN,—NO₂, —CO₂R⁸, —CON(R⁸R⁹), —NCO—R⁸, or halogen; n6 and n7 each is,independently for each occurrence, 0, 1, or 2; wherein said heterocyclylis azepinyl, benzimidazolyl, benzisoxazolyl, benzofurazanyl,benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl,benzothienyl, benzoxazolyl, chromanyl, cinnolinyl, dihydrobenzofuryl,dihydrobenzothienyl, dihydrobenzothiopyranyl, dihydrobenzothio-pyranylsulfone, furyl, imidazolidinyl, imidazolinyl, imidazolyl, indolinyl,indolyl, isochromanyl, isoindolinyl, isoquinolinyl, isothiazolidinyl,isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl,oxadiazolyl, 2-oxoazepinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyridyl N-oxide,quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolinyl,tetrahydro-quinolinyl, thiamorpholinyl, thiamorpholinyl sulfoxide,thiazolyl, thiazolinyl, thienofuryl, thienothienyl, or thienyl; andwherein said aryl is phenyl or naphthyl; provided that: when n1=1, R¹⁰is C and R⁶ is H, then R¹⁰ and R⁷ can be taken together to form

when n1=1, R¹⁰ is C, and R⁷ is ═O, —H, or ═S, then R¹⁰ and R⁶ can betaken together to form

wherein X¹, X², and X³ each is, independently, H, halogen, —NO₂,—NCO—R⁸, —CO₂R⁸, —CN, or —CON(R⁸R⁹); and when R¹ is N(R²⁴R²⁵), then n3is 1, n4 and n5 each is 0, Z is a bond, and R³ and R¹¹ can be takentogether to form

wherein n2 is 1-6, and X⁴ and X⁵ each is, independently, H, (C₁₋₆)alkyl,or aryl, or X⁴ and X⁵ can be taken together to form (C₃₋₆)cycloalkyl; ora pharmaceutically acceptable salt thereof.
 3. A pharmaceuticalcomposition according to claim 2, wherein: R¹ is

or N(R²⁴R²⁵); and X is CH(R¹¹)_(n3)(CH₂)_(n4) or Z, wherein when X is Z,Z is O, S, or N(R¹²); or a pharmaceutically acceptable salt thereof. 4.A pharmaceutical composition according to claim 3, wherein: R¹ is

X is CH(R¹¹)_(n3)(CH₂)_(n4); and n1 is 0; or a pharmaceuticallyacceptable salt thereof.
 5. A pharmaceutical composition according toclaim 3, wherein: R¹ is

n3, n4, and n5 each is 0; Z is a bond; Y is, independently for eachoccurrence, CO or CS; and n1 is 0; or a pharmaceutically acceptable saltthereof.
 6. A pharmaceutical composition according to claim 3, wherein:R¹ is

R⁶ is H; n1 is 1; R⁷ and R¹⁰ are taken together to form

n3 is 1 and R¹¹ is H; Z is O or a bond; n5 is 0; and Y is CO, CH₂, or abond; or a pharmaceutically acceptable salt thereof.
 7. A pharmaceuticalcomposition according to claim 3, wherein: R¹ is N(R²⁴R²⁵); n1 is 0; n3is 1; n4 is 0; n5 is 0; Y is CO or CS; Z is a bond; and R³ and R¹¹ aretaken together to form

or a pharmaceutically acceptable salt thereof.
 8. A pharmaceuticalcomposition according to claim 3, wherein said farnesyl transferaseinhibitor is a compound of formula I, wherein: R¹ is

R⁷ is H or ═O; n1 is 1; R⁶ and R¹⁰ are taken together to form

n3 is 1 and R¹¹ is H; n5 is 0; Y is CO or CH₂; and Z is O or a bond; ora pharmaceutically acceptable salt thereof.
 9. A pharmaceuticalcomposition according to claim 2, wherein said farnesyl transferaseinhibitor is:8-butyl-7-(3-(imidazol-5-yl)-1-oxopropyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;8-butyl-2-(2-hydroxyphenyl)-7-(imidazol-4-yl-propyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;8-butyl-7-(4-imidazolylpropyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;7-(2-(imidazol-4-yl)-1-oxo-ethyl)-2-(2-methoxyphenyl)-8-(1-methylpropyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;2-(2-methoxyphenyl)-8-(1-methylpropyl)-7-(1-oxo-2-(1-(phenylmethyl)-imidazol-5-yl)ethyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;2-(2-methoxyphenyl)-8-(1-methylpropyl)-7-(2-(1-phenylmethyl)-imidazol-5-yl)ethyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;7-(2-(1-(4-cyanophenylmethyl)-imidazol-5-yl)-1-oxo-ethyl)-2-(2-methoxyphenyl)-8-(1-methylpropyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;7-((1H-imidazol-4-yl)methyl)-2-(2-methoxyphenyl)-8-(1-methylpropyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;7-((4-imidazolyl)carbonyl)-2-(2-methoxyphenyl)-8-(1-methylpropyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;7-(1-(4-cyanophenylmethyl)-imidazol-5-yl)methyl-2-(2-methoxyphenyl)-8-(1-methylpropyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;7-(2-(4-cyanophenylmethyl)-imidazol-5-yl)-1-oxo-ethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine;5-butyl-7-(2-(4-cyanophenylmethylimidazol-5-yl)-1-oxo-ethyl)-2-phenyl-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;6-butyl-7-(2-(4-cyanophenylmethylimidazol-5-yl)-1-oxo-ethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine;6-butyl-7-(2-(4-cyanophenylmethylimidazol-5-yl)-1-oxo-ethyl)-2-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine;5-butyl-7-(2-(1-(4-cyanophenylmethyl)-imidazole-5-yl)-1-oxo-ethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;7-(2-(1-(4-cyanophenylmethyl)-imidazole-5-yl)-1-oxo-ethyl)-8-(cyclohexylmethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;5-butyl-7-(2-(1H-imidazole-5-yl)-1-oxo-ethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazine;7-(2-(4-cyanophenylmethyl)-imidazol-5-yl)-1-oxo-ethyl)-2-(2-(phenylmethoxy)-phenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine;or2-(2-butoxyphenyl)-7-(2-(4-cyanophenylmethyl)-imidazol-5-yl)-1-oxo-ethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine;or a pharmaceutically acceptable salt thereof.
 10. A pharmaceuticalcomposition according to claim 2, wherein said farnesyl transferaseinhibitor is:1,2-dihydro-1-((1H-imidazol-4-yl)methyl)-4-(2-methoxyphenyl)-imidazo[1,2-c][1,4]benzodiazepine;1-(2-(1-(4-cyanophenylmethyl)imidazol-4-yl)-1-oxoethyl)-1,2-dihydro-4-(2-methoxyphenyl)-imidazo[1,2-c][1,4]benzodiazepine;9-bromo-1-(2-(1-(4-cyanophenylmethyl)imidazol-4-yl)-1-oxoethyl)-1,2-dihydro-4-(2-methoxyphenyl)-imidazo[1,2-c][1,4]benzodiazepine;9-Chloro-1-(2-(1-(4-cyanophenylmethyl)imidazol-4-yl)-1-oxoethyl)-1,2-dihydro-4-(2-methoxyphenyl)-imidazo[1,2-c][1,4]benzodiazepine;10-Bromo-1-(2-(1-(4-cyanophenylmethyl)imidazol-4-yl)-1-oxoethyl)-1,2-dihydro-4-(2-methoxyphenyl)-imidazo[1,2-c][1,4]benzodiazepine;1-(2-(1-(4-cyanophenylmethyl)imidazol-4-yl)-1-oxoethyl)-1,2-dihydro-8-fluoro-4-(2-methoxyphenyl)-imidazo[1,2-c][1,4]benzodiazepine;or or a pharmaceutically acceptable salt thereof.
 11. A pharmaceuticalcomposition according to claim 10, wherein said farnesyl transferaseinhibitor is:1-(2-(1-(4-cyanophenylmethyl)imidazol-4-yl)-1-oxoethyl)-1,2-dihydro-4-(2-methoxyphenyl)-imidazo[1,2-c][1,4]benzodiazepine;9-bromo-1-(2-(1-(4-cyanophenylmethyl)imidazol-4-yl)-1-oxoethyl)-1,2-dihydro-4-(2-methoxyphenyl)-imidazo[1,2-c][1,4]benzodiazepine;9-Chloro-1-(2-(1-(4-cyanophenylmethyl)imidazol-4-yl)-1-oxoethyl)-1,2-dihydro-4-(2-methoxyphenyl)-imidazo[1,2-c][1,4]benzodiazepine;10-Bromo-1-(2-(1-(4-cyanophenylmethyl)imidazol-4-yl)-1-oxoethyl)-1,2-dihydro-4-(2-methoxyphenyl)-imidazo[1,2-c][1,4]benzodiazepine;1-(2-(1-(4-cyanophenylmethyl)imidazol-4-yl)-1-oxoethyl)-1,2-dihydro-8-fluoro-4-(2-methoxyphenyl)-imidazo[1,2-c][1,4]benzodiazepine.12. A pharmaceutical composition according to claim 2, wherein saidfarnesyl transferase inhibitor is:7-(2-amino-1-oxo-3-thiopropyl)-8-(mercaptoethyl)-2-(2-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2a]pyrazinedisulfide; or a pharmaceutically acceptable salt thereof.
 13. Apharmaceutical composition according to claim 2, wherein said farnesyltransferase inhibitor is:5-(2-(1-(4-cyanophenylmethyl)-imidazol-5-yl)-1-oxo-ethyl)-5,6-dihydro-2-phenyl-1H-imidazo[1,2-a][1,4]benzodiazepine;or a pharmaceutically acceptable salt thereof.
 14. A pharmaceuticalcomposition according to claim 2, wherein said farnesyl transferaseinhibitor is:1,2-dihydro-1-(2-(imidazol-1-yl)-1-oxoethyl)-4-(2-methoxyphenyl)imidazo[1,2a] [1,4]benzodiazepine;1,2-dihydro4-(2-methoxyphenyl)-1-(2-(pyridin-3-yl)-1-oxoethyl)imidazo[1,2a][1,4]benzodiazepine; or1,2-dihydro-4-(2-methoxyphenyl)-1-(2-(pyridin-4-yl)-1-oxoethyl)imidazo[1,2a][1,4]benzodiazepine; or a pharmaceutically acceptable saltthereof.
 15. A pharmaceutical composition according to claim 2, whereinsaid farnesyl transferase inhibitor is:

or a pharmaceutically acceptable salt thereof.
 16. A pharmaceuticalcomposition according to claim 2, wherein said farnesyl transferaseinhibitor is:

or a pharmaceutically acceptable salt thereof.
 17. A pharmaceuticalcomposition according to claim 16, wherein said farnesyl transferaseinhibitor is:

or a pharmaceutically acceptable salt thereof.
 18. A pharmaceuticalcomposition according to claim 17, wherein said anthracyclin isdoxorubicin, daunorubicin, epirubicin, idarubicin, or amrubicin, or apharmaceutically acceptable salt thereof.
 19. A pharmaceuticalcomposition according to claim 17, wherein said anthracyclin isdoxorubicin, or a pharmaceutically acceptable salt thereof.
 20. Apharmaceutical composition according claim 1, wherein said anthracyclinis doxorubicin, daunorubicin, epirubicin, idarubicin, or amrubicin, or aprodrug thereof, or a pharmaceutically acceptable salt of saidanthracyclin or of said anthracyclin prodrug.
 21. A pharmaceuticalcomposition according to claim 20, wherein said anthracyclin isdoxorubicin, or a pharmaceutically acceptable salt thereof.
 22. A methodof decreasing the rate of proliferation of nasopharyngeal carcinomacells, said method comprising contacting said nasopharyngeal cells witha pharmaceutical composition according to any one of claims 18-21.23-25. (canceled)
 26. A method of treating nasopharyngeal carcinoma in apatient, said method comprising administering to said patient apharmaceutical composition according to any one of claims 18-21. 27-29.(canceled)
 30. A method of treating nasopharyngeal carcinoma in apatient, said method comprising administering to said patient aneffective amount of one or more farnesyl transferase inhibiting compoundin combination with an effective amount of one or more anthracyclinecompound, wherein said effective amount of said farnesyl transferaseinhibiting compound or compounds and of said anthracycline compound orcompounds are effective in combination to treat said nasopharyngealcarcinoma.
 31. A method according to claim 30 wherein said patient is amammal.
 32. A method according to claim 31 wherein said patient is ahuman being.
 33. A method according to claim 32 wherein said farnesyltransferase inhibiting compound and said anthracycline compound areadministered substantially simultaneously.
 34. A pharmaceutical kitcomprising a composition according to claim 18 and instructions for useof said composition for the treatment of nasopharyngeal carcinoma.35-37. (canceled)
 38. A kit comprising: a) a first unit dosage formcomprising a farnesyl transferase inhibitor, a prodrug thereof or apharmaceutically acceptable salt of said farnesyl transferase inhibitoror of said farnesyl transferase inhibitor prodrug and a pharmaceuticallyacceptable carrier, vehicle or diluent; b) a second unit dosage formcomprising an anthracycline, a prodrug thereof or a pharmaceuticallyacceptable salt of said anthracycline or of said anthracycline prodrugand a pharmaceutically acceptable carrier, vehicle or diluent; and c) acontainer. 39-40. (canceled)